Role of IL-12 family cytokines in human autoimmune Uveitis

IL-12家族细胞因子在人类自身免疫性葡萄膜炎中的作用

• 批准号: 7968292
• 负责人: Charles E Egwuagu
• 金额: $ 36.75万
• 依托单位: NATIONAL EYE INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7968292
• 关键词: Affinity; Antibodies; Autoimmune Process; Autoimmunity; Binding; Cells; Chronic; Colitis; Collagen Arthritis; Daclizumab; Development; Disease; Etiology; Experimental Autoimmune Encephalomyelitis; Eye; Eye diseases; Family; Host Defense; Human; Immune; Immunity; Inbred Strains Mice; Inflammation; Inflammatory; Interleukin 2 Receptor; Interleukin-12; Interleukin-17; Interleukin-2; Maintenance; Mediating; Modeling; Mus; Pathogenesis; Pathology; Peripheral Blood Mononuclear Cell; Phenotype; Photoreceptors; Play; Reporting; Retinal; Retinal Ganglion Cells; Role; Scleritis; T-Lymphocyte; Th1 Cells; Tissues; Uveitis; autoimmune uveitis; cytokine; effective therapy; human disease; interest; interleukin-23; men; mouse model; novel; prevent; therapeutic target

The IL-12 family is comprised of three types of heterodimeric cytokines, IL-12, IL-23 and IL-27. Prior to the discovery of IL-23 and IL-27, IL-12 was thought to be the cause of several chronic inflammatory diseases because of its unique ability to induce differentiation of naive T-cells towards IFN?-secreting Th1 phenotype. However, IL-23 promotes differentiation and/or maintenance of the highly pathogenic ThIL-17 subtype and is now thought to be the primary etiologic agent in several chronic inflammatory diseases. IL-27 promotes the differentiation of naive T cells into Th1 cells but its role in host defense and immune-mediated diseases is largely unknown. Discovery of antagonism between these cytokines have led to increased interest in the roles played by these cytokines in the etiology and treatment of several chronic inflammatory diseases including uveitis. Recent reports have implicated ThIL17 cells in the pathogenesis of a number of immune-mediated diseases including experimental allergic encephalomyelitis (EAE), collagen-induced arthritis (CIA) and colitis. However, most of these studies have been in inbred mouse strain and involvement of ThIL17 cells in human diseases has not been firmly established. In this study, we examined whether ThIL17 cells are involved in two human ocular inflammatory diseases (uveitis and scleritis) and have also investigated the role of this T-cell subtype in the mouse model of human uveitis, experimental uveitis model (EAU). Uveitis is a T-cell mediated intraocular inflammatory disease of presumed autoimmune etiology. Although inhibiting the formation of high affinity IL-2 receptor (IL-2R) by a humanized anti-Tac antibody (Daclizumab) is effective therapy in treatment of these potentially binding ocular diseases, pathogenic T-cell subtypes that cause uveitis or mechanism of IL-2R action remain known. We show that a major difference between mice and "men" in this study is that ThIL17 cells are detected in normal peripheral blood mononuclear cells (PBMC) of humans but not mice. However, IL-17 is elevated in uveitis, scleritis and EAU and we show that its induction of TNFa expression in retinal cells may contribute to the pathology of chronic inflammatory disease of the eye. We further show that IL-27 is constitutively expressed in retinal ganglion and photoreceptor cells, is upregulated by IFNg and inhibits proliferation of ThIL-17-cells. These findings suggest a novel mechanism by which Th1-cells may mitigate uveitis by antagonizing ThIL17-phenotype through IFN?-mediated induction of IL-27 in target tissue. This study showing that IL-2 promotes ThIL17-cells expansion provides explanations for efficacy of anti-IL2R therapy in uveitis and suggests that antagonism of ThIL17-cells by IFNg/IL-27 maybe exploited in treating chronic inflammation.

IL-12家族由三种异二聚体细胞因子组成，即IL-12、IL-23和IL-27。在IL-23和IL-27被发现之前，IL-12被认为是多种慢性炎症性疾病的病因，因为它具有诱导原始T细胞向分泌干扰素的Th1表型分化的独特能力。然而，IL-23促进高致病性Thil-17亚型的分化和/或维持，目前被认为是几种慢性炎症性疾病的主要病原体。IL-27促进初始T细胞向Th1细胞分化，但其在宿主防御和免疫介导性疾病中的作用尚不清楚。这些细胞因子之间的拮抗作用的发现使人们对这些细胞因子在包括葡萄膜炎在内的几种慢性炎症性疾病的病因和治疗中所起的作用产生了越来越大的兴趣。最近的报道表明ThIL17细胞参与了许多免疫介导性疾病的发病，包括实验性变态反应性脑脊髓炎(EAE)、胶原诱导性关节炎(CIA)和结肠炎。然而，这些研究大多是在近交系小鼠身上进行的，ThIL17细胞与人类疾病的关系尚未得到确凿的证实。在这项研究中，我们研究了ThIL17细胞是否与两种人类眼部炎症性疾病(葡萄膜炎和巩膜炎)有关，并研究了这一T细胞亚型在人葡萄膜炎小鼠模型-实验性葡萄膜炎模型(EAU)中的作用。葡萄膜炎是一种T细胞介导的眼内炎症性疾病，推测为自身免疫性病因。虽然用人源化抗Tac抗体(Daclizumab)抑制高亲和力IL-2受体(IL-2R)的形成是治疗这些潜在结合性眼病的有效方法，但引起葡萄膜炎的致病T细胞亚型或IL-2R的作用机制仍是已知的。我们发现，在这项研究中，小鼠和“人”之间的一个主要区别是在人的正常外周血单个核细胞(PBMC)中检测到ThIL17细胞，而在小鼠中没有检测到。然而，IL-17在葡萄膜炎、巩膜炎和EAU中升高，我们发现其诱导视网膜细胞表达TNFa可能参与了眼部慢性炎症性疾病的病理过程。我们进一步证明IL-27在视网膜神经节和光感受器细胞中有结构性表达，被IFNG上调，并抑制Thil-17细胞的增殖。这些发现提示了一种新的机制，Th1细胞可以通过干扰素？介导的靶组织中IL-27的诱导来对抗ThIL17表型，从而减轻葡萄膜炎。本研究表明IL-2促进ThIL17-细胞的增殖，为抗IL2R治疗葡萄膜炎的疗效提供了解释，并提示IFNG/IL-27对ThIL17-细胞的拮抗作用可能用于治疗慢性炎症。